Oxford Molecular Genetics Laboratory
Genetics Laboratories, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LE
www.ouh.nhs.uk/geneticslab
FAMILIAL BENIGN HYPOCALCIURIC HYPERCALCAEMIA (FHH)
OMIM: 145980/145981/600740
INTRODUCTION
Familial benign hypocalciuric hypercalcaemia is an autosomal dominant disorder of extracellular calcium homeostasis,
characterised by lifelong hypercalcaemia with inappropriately low urinary calcium excretion (mean urinary
calcium:creatinine clearance ratio <0.01)
Identification of pathogenic variants in the genes responsible for FHH can confirm the diagnosis based on
clinical/biochemical presentation. This can assist in directing patient management and whether surgical intervention is
required.
It is a genetically heterogeneous condition where the types are clinically indistinguishable. To date the following genes
have been identified as causative of FHH:
CASR: Pathogenic loss of function mutations in the CASR gene account for FHH type1 (FHH1). ~65% of individuals
with definite FHH are reported to have a pathogenic variant in this gene.
GNA11: pathogenic variants in this gene are causative of FHH type 2 (FHH2). Nesbit et al, 2013, NEJM, identified
pathogenic GNA11 variants in >10% CASR & AP2S1 negative FHH patients (although the cohort tested was small).
AP2S1: The molecular basis of FHH type 3 (FHH3) has been identified as mutation of codon p.Arg15 of the AP2S1
gene. >20% of CASR negative FHH patients have this mutation (Nesbit et al, Jan 2013, Nature Genetics).
TESTING
Diagnostic:
Presymptomatic/confirmation:
Patients with a consistent “Clinical/Biochemical diagnosis”.
Individuals at risk of developing FHH/ relatives of individuals in whom a pathogenic
variant has been identified.
REFERRALS
All samples MUST be accompanied by a completed ‘Hypercalcaemia and Hyperparathyroidism’ pre-referral
form (click here)
o Clinical guidance is available from Professor Rajesh Thakker, Professor of Medicine, OCDEM, Churchill Hospital
(rajesh.thakker@ndm.ox.ac.uk).
o UK diagnostic referrals are accepted from Clinical Genetics, Endocrinology and consultants from other relevant
specialties.
o Familial mutation referrals should ideally be referred through/in collaboration with Clinical Genetics departments.
o Requests for familial mutation testing should either be discussed with the laboratory in advance or be
accompanied by details regarding the known pathogenic mutation in the family.
STRATEGY & TECHNICAL INFORMATION
o Mutation screening in diagnostic referrals is undertaken by fluorescent sequencing of the entire coding region and
intron/exon boundaries of the selected gene (CASR and GNA11), or specific analysis of codon p.Arg15 in AP2S1.
o Testing can be undertaken sequentially or simultaneous analysis of the 3 genes is available.
o When a pathogenic mutation has been identified in an individual, subsequent testing of family members
(presymptomatic or diagnostic confirmation) involves testing for the familial mutation only.
TARGET REPORTING TIMES
Diagnostic test:
Presymptomatic/Familial Mutation test:
40 days
10 days
N.B. Details are correct for the date of printing only – last updated 14/07/2015